Immunostainings of tissue biopsy specimenīiopsies were cryosectioned (8 μm), fixed in 2% formaldehyde and immunostained as previously described (Norrby-Teglund et al., 2001 Thulin et al., 2006 Johansson et al., 2009). pyogenes infections revealed a significant correlation between increased HMGB1 and severity of tissue infection. Analyses of tissue biopsies from patients with varying severity of S. Here we set out to gain insight into events occurring in the microenvironment at the infected tissue site by delineating HMGB1 responses in acute necrotic STIs caused by Streptococcus pyogenes. Although a number of bacteria can cause NSTI, the main causative microbes are Streptococcus pyogenes and Staphylococcus aureus (McHenry et al., 1995). Despite modern medicine, the mortality associated with necrotizing soft tissue infections (NSTIs) is high, often exceeding 30% (Anaya et al., 2005 Marwick et al., 2011). These are life-threatening infections where the vast majority of patients require intensive care and extensive surgical interventions. However, little is known about local HMGB1 responses in acute necrotic bacterial soft tissue infections (STIs), such as necrotizing fasciitis. Subsequently, elevated levels of HMGB1 have been readily detectable in circulation of patients with severe sepsis and septic shock (Sunden-Cullberg et al., 2005). In sepsis, murine experimental data demonstrated a critical role of HMGB1 as a late mediator contributing to mortality (Wang et al., 1999). HMGB1 has been implicated in a variety of clinical conditions including arthritis, sepsis and chronic kidney disease (Harris et al., 2012). Importantly post-translational modifications, including acetylation, phosphorylation, methylation and redox state of the cysteine residues, influence receptor interactions, and thereby, elicited responses (Harris et al., 2012 Venereau et al., 2012 Yang et al., 2012). Studies have suggested differential responses depending on receptor engagement, with TLR4 being involved in cytokine release (Yang et al., 2010) whereas RAGE is involved in cell migration (Penzo et al., 2010). Several receptors have been shown to interact with HMGB1 including toll-like receptor 4 (TLR4), the receptor for advanced glycation end products (RAGE) and CD24-Siglec-10 (Lotze and Tracey, 2005 Tian et al., 2007 Chen et al., 2009). Extracellular HMGB1 has been reported to act as an alarmin with ability to activate the immune system leading to cell proliferation, adhesion, migration, and cytokine release (Harris et al., 2012). High mobility group box protein 1 (HMGB1) is a ubiquitously expressed, highly conserved nuclear protein that is released either through active secretion by innate immune cells, enterocytes and hepatocytes or through passive release by injured, autophagic or necrotic cells (Bianchi et al., 1989 Tsung et al., 2007 Livesey et al., 2009 Skinner, 2010 Tang et al., 2010 Thomas and Stott, 2012). Taken together, the findings provide the first in vivo evidence that HMGB1 is abundant at the local site of severe bacterial STIs and its levels correlated to severity of infections hence, indicating its potential value as a biomarker for tissue pathology. The data furthermore provided in vivo support that HGMB1 may form immunostimulatory complexes with IL-1β. In vitro transmigration experiments showed a chemotactic effect of HMGB1 on neutrophils. Dual staining's visualized HMGB1 in areas close to, but not overlapping, with neutrophils, indicating a potential chemotactic role. The results demonstrated infection triggered release of HMGB1. To further verify macrophages as main source of activation triggered HMGB1 release, human macrophages were infected with clinical S. Confocal microscopy of sections co-stained for HMGB1 and cell markers revealed both extracellular and cytoplasmic HMGB1, the latter of which was found predominantly in macrophages. HMGB1 expression increased in parallel to disease severity and was significantly higher in necrotizing fasciitis than in erysipelas ( p = 0.0023). pyogenes, and inflammatory cell infiltrates and results quantified by acquired computerized image analysis (ACIA). Tissue sections were immunostained for HMGB1, S. Flowjo acquired by bd skin#To explore this, tissue biopsies were collected from patients with varying severity of Streptococcus pyogenes skin and STIs, including erysipelas, cellulitis, and necrotizing fasciitis. We hypothesized that the local HMGB1 response is excessive in severe soft tissue infections (STIs), which are characterized by necrosis and hyperinflammation. However, little is known about HMGB1 in necrotizing bacterial infections. Extracellular High Mobility Group Box 1 (HMGB1) has been associated with acute and chronic inflammatory conditions.
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